Patients diagnosed with malignant pleural mesothelioma are usually given a very grim prognosis, and in the past had very few treatment options.  However, due to the pioneering efforts of Dr. David Sugarbaker at the International Mesothelioma Program (IMP) at Brigham and Women’s Hospital in Boston, patients have a much better prognosis with surgery aimed at removing the tumor, followed by chemotherapy to kill any remaining cells.  These procedures are called cytoreductive (or debulking) surgery and intrathoracic heated chemotherapy administered during surgery.

Surgery to Remove the Tumor

Cytoreductive surgery falls into two categories:  (1) extrapleural pneumonectomy that involves the removal of the affected lung, and (2) pleurectomy and decortication which is the removal of the pleura and as much tumor tissue as possible.  The type of surgery that a patient receives at the IMP depends upon how early the mesothelioma was diagnosed and the extent to which the disease has spread.  It is part of the preoperative protocol at the International Mesothelioma Program to perform a procedure called a mediastinoscopy, to biopsy the patient’s lymph nodes in the  mid-chest area or mediastinum.  This procedure tells the physicians at the IMP the extent to which the malignant mesothelioma has spread.

If the patient’s malignant mesothelioma is discovered early enough, Dr. Sugarbaker may perform an extrapleural pneumonectomy.  Not only is the affected lung removed, but the diaphragm, pleura, and pericardium are also surgically removed.  The diaphram and other structures in the chest are re-built using Gortex, which is a synthetic gas-permeable membrane.   The other surgery, a pleurectomy/decortication is used to removed the diseased pleura and as much of the patient’s mesothelioma tumor as possible.

Chemotherapy Drugs Administered Immediately

At the International Mesothelioma Program, following either the extrapleural pneumonectomy or the pleurectomy/decortication, the patient’s chest cavity is infused with a lavage (washing out the organs) of heated chemotherapy drugs.  Researchers and physicians at the IMP have determined that there is much greater chemotherapy penetration when the drugs are heated and washed directly over the affected area compared to being delivered intravenously.  The purpose of the intracavitary heated chemotherapy lavage is to kill the malignant mesothelioma cells that might be left behind after surgery and that cannot be seen by the surgeon.

Success With Dr. Sugarbaker’s Techniques

Dr. Sugarbaker and his team have been very successful in using cytoreductive surgery and intracavitary heated chemotherapy in prolonging the lives of malignant pleural mesothelioma patients.  Dr. Sugarbaker reports some patients surviving five to 10 years using this combination of surgery and heated chemotherapy.

Clinic Trials Recruiting Pleural Mesothelioma Patients

Brigham and Women’s Hospital, in collaboration with the Dana-Farber Cancer Institute in Boston, are currently recruiting patients with malignant pleural mesothelioma for two clinical trials.  The first is a Phase I clinical trial that will study the effects of extrapleural pneumonectomy/pleurectomy decortication followed by a combination of heated chemotherapy drugs Cisplatin and Gemcitabine administered during surgery.  The second is a Phase II clinical trial that will study the effects of pleurectomy/decortication combined with intraoperative heated Cisplatin, then followed by an intravenous administration of sodium thiosulfate to reduce the effects of the Cisplatin.

Patients at the International Mesothelioma Program (IMP) at the Brigham and Women’s Hospital in Boston, Massachusetts who have a confirmed diagnosis of malignant pleural mesothelioma routinely undergo a series of tests to determine the type of surgery they need.  One of these tests is called a “cervical mediastinoscopy,” which is used to biopsy the patient’s lymph nodes.  This test helps assess how far the cancer has spread.  This information, in conjunction with other test results, is used to help determine if the patient is a candidate for either a pleurectomy or an extrapleural pneumonectomy.

Cervical Mediastinoscopy Used to Biopsy Lymph Nodes

The International Mesothelioma Program  is one of the leading treatment centers for malignant pleural mesothelioma.  According to Dr. David Sugarbaker, who is Chief of Thoracic Surgery at the Brigham and Women’s Hospital and the founder and Director of the International Mesothelioma Program, the IMP consulted with over 300 malignant pleural mesothelioma patients last year and performed over 160 surgeries.  As part of the screening process for surgical candidates, a cervical mediastinoscopy is performed at the hospital to determine if the cancer has spread to the mediastinal lymph nodes.

A cervical mediastinoscopy is a hospital procedure performed under general anesthesia used to biopsy lymph nodes in patients with malignant pleural mesothelioma.  The surgeon makes an incision in the patient’s neck at the top of the sternum.  The mediastinoscope, which is a thin tube with a light and surgical instruments, is then placed through the incision where tissue samples are taken from the mediastinal lymph nodes.  The patient’s biopsied tissue is analyzed by a pathologist to determine if the malignant mesothelioma has spread to the mediastinal lymph nodes.  The IMP’s surgical team, led by Dr. Sugarbaker, uses this information to determine whether the patient is a surgical candidate and if so, the type of surgery that will be performed.

Published Research on Importance of Cervical Mediastinoscopy

In 1999, Dr. Sugarbaker and his colleagues published an article entitled, “Resection Margins, Extrapleural Nodal Status, and Cell Type Determine Postoperative Long-Term Survival In Trimodality Therapy of Malignant Pleural Mesothelioma:  Results in 183 Patients” in the Journal of Thoracic and Cardiovascular Surgery. Dr. Sugarbaker described the importance of mediastinoscopy as a staging tool for patients with malignant pleural mesothelioma.  A similar conclusion concerning the importance of cervical mediastinoscopy was reached by British physicians in a published article entitled, “The Case for Routine Cervical Mediastinoscopy Prior to Radical Surgery for Malignant Pleural Mesothelioma” in the European Journal of Cardio-Thoracic Surgery in 2004.

Treatment of malignant mesothelioma has been extremely difficult.  Not only is malignant mesothelioma resistant to most forms of chemotherapy drugs, but even when the mesothelioma tumor responds to the standard protocol of treatment with Alimta (Pemetrexed) and Cisplatin, the malignant mesothelioma eventually becomes resistant to these drugs as well.  It is not known whether the malignant mesothelioma cells mutate to become resistant or whether there are portions of the mesothelioma tumor that were resistant to begin with, which then proliferate once the non-resistant tumor cells are killed by the Pemetrexed and Cisplatin combination.

Oxaliplatin

In the search for a cure for malignant mesothelioma, researchers are looking at various other chemotherapy drugs that might be used as a secondary treatment protocol to follow the first-line treatment with Pemetrexed and Cisplatin.  One such drug that is being considered is Oxaliplatin, which goes by the trade name Eloxatin.  Oxaliplatin (Eloxatin) was first developed by Dr. Yoshinori Kidani at Nagoya City University in 1976.  Oxaliplatin (Eloxatin) is an alkylating agent that works by causing damage to the DNA of cancer cells.  Other alkylating agents that are used in the treatment of malignant mesothelioma are Carboplatin and Cisplatin.

Oxaliplatin (Eloxatin) and Gemcitabine Tested as a Second-Line Treatment of Malignant Pleural Mesothelioma in a Clinical Trial

On December 18, 2008,  the Journal of Occupational Medicine & Toxicology, published the article entitled Gemcitabine Combined with Oxaliplatin in Pretreated Patients with Malignant Pleural Mesothelioma: An Observational Study.  This paper was based on a clinical trial of 29 patients who were diagnosed with malignant pleural mesothelioma and had been previously treated with Cisplatin and Pemetrexed.  These patients were given a combination of Gemcitabine and Oxaliplatin as a second-line treatment for their malignant pleural mesothelioma.  It was found that when at least three cycles of Gemcitabine and Oxaliplatin were given to these patients in this clinical trial, 6.9% obtained partial remission and another 37.9% achieved stable disease.  This amounted to a malignant pleural mesothelioma control rate of 44.8%.  Just as important, the patients tolerated the treatment well with no significant toxicities or side effects reported in any of the patients.  This drug combination provides great hope and promise in mesothelioma treatment.

New Clinical Trial Using Oxaliplatin (Eloxatin) and Bortezomib (Velcade) in Patients with Malignant Pleural Or Peritoneal Mesothelioma

Columbia University opened a new clinical trial that began recruiting patients with malignant pleural mesothelioma or peritoneal mesothelioma in October 2009 that will use Bortezomib (Velcade) and Oxaliplatin (Eloxatin) for treatment.  To be included in this clinical trial, patients must have received only one prior form of chemotherapy.  Patients who received a combination of Pemetrexed plus Cisplatin or Pemetrexed plus Carboplatin will qualify for this clinical trial.

The International Mesothelioma Interest Group (iMig) is an organization composed of  health professionals and researchers who have an interest in malignant mesothelioma.  This year the iMig will hold its 10th International Conference from August 31, 2010 to September 3, 2010 at the Kyoto International Conference Center in Kyoto, Japan.  The conference will be hosted by Hyogo College of Medicine, with Dr. Takashi Nagano serving as conference chair.  There will be 14 educational lectures and over 30 keynote lectures by doctors and researchers from around the world who specialize in mesothelioma.  Membership in iMig is not required to attend the conference, although certain workshops may not be open for everyone’s participation.

Some of the Planned Educational and Keynote Lectures

Dr. David Sugarbaker, thoracic surgeon at the International Mesothelioma Program (IMP) at Brigham and Women’s Hospital in Boston, Massachusetts, will lecture on Extra Pleural Pneumonectomy (EPP) and Intraoperative Heated Chemotherapy.  His brother, Dr. Paul Sugarbaker, who is the director of Surgical Oncology at the Washington Cancer Institute in Washington, D.C., will speak on his specialty, Peritoneal Mesothelioma.  Another noteworthy United States surgeon, Dr. Harvey Pass, who is chief of Thoracic Surgery and Thoracic Oncology of the Department of Cardiovascular Surgery, New York University School of Medicine and Comprehensive Cancer Center, will present a lecture entitled Surgical Approach; Thoracoscopy and Video-Assisted Thoracoscopic Surgery (VATS).

International speakers include Dr. Luciano Mutti of Italy who will lecture on New Pathways and Molecular Targeted Therapy.  Dr. Mutti has published papers on malignant mesothelioma with Dr. Giovanni Gaudino, a researcher at the Cancer Research Center of Hawaii (CRCH).  Dr. Takeharu Yamanaka of Japan will present a lecture on Biostatistics for Mesothelioma Clinical Trials.  Dr. Christopher Lee from Canada will lecture on Maintenance Therapy; Transitioning From 1st-Line Cisplatin Plus Pemetrexed Treatment in Malignant Pleural Mesothelioma (MPM).

There will be a number of other international lecturers who will speak on topics that range from the early detection to molecular oncogenesis to the most current treatment options of malignant mesothelioma.

DNA double helix

In 1953, two British researchers, James D. Watson and Francis Crick, won the race to a Nobel Prize by unlocking the structure of DNA (deoxyribonucleic acid).  Watson and Crick discovered the double-helix, made up of two inter-connected, spiral staircase-like structures.  This watershed event has allowed scientists to make huge strides in human genetic research.  It is the opinion of the International Mesothelioma Program (IMP) of the Brigham and Women’s Hospital in Boston, Massachusetts that understanding genetic sequencing and mutations may hold the key to curing malignant mesothelioma.

DNA is found in chromosomes which are in every single cell in the human body, including cancer cells.  Four nucleotides in DNA are arranged to form genes.  Genes control cell proteins that send signals to the cell to perform various tasks in cell growth.  For example, the proteins will signal cells to stop growing or to die when appropriate, a process known as apoptosis.  However, in cancer cells, genetic mutations can cause proteins to improperly signal cells to continue to divide and grow, when they should have stopped.

Genomics is the study of genes and their function.  Understanding genes and the proteins that signal cells to perform their functions is one of the keys to understanding human disease.  Researchers at the IMP feel that the disease malignant mesothelioma, which is resistant to treatment, can be cured if the genetic mutations of the malignant cells can be understood.

Genomes for Lung Cancer and Melanoma Mapped

After months of work, researchers in England successfully mapped the genomes for two deadly malignancies – lung cancer and melanoma.  The results of this study were published in the well-respected scientific journal Nature in 2009 by the Cancer Genome Project at the Wellcome Trust Sanger Institute.  If the genomes for an individual patient’s tumor can be mapped, this could lead to individualized treatment, because everyone’s cancer contains different genetic mutations.  Unfortunately, the cost to do genome mapping is still prohibitively expensive to do on an individual basis.

Genentech and IMP Map Genomes from Malignant Mesothelioma

The IMP is working with the biotechnology company Genentech, Inc. to map the genomes of cells taken from patients with malignant pleural mesothelioma.  Genentech,  purchased in 2009 by pharmaceutical giant the Roche Group, provides the genomic technology for this research.

According to Gavin Gordon, Ph.D. of the IMP, the genomic mapping includes not only mutated cells, but also the normal cells found in all cancers.  These normal cells are essential to providing the nutrients and blood supply to the tumor which allow it to grow.   In an interview with attorney Jeffrey T. Ono of  Galiher DeRobertis Ono, Dr. Gavin said that the cost of doing genomic mapping for malignant mesothelioma cells has gone from around $2.5 million to approximately $250,000.  These costs would still prevent many mesothelioma patients from having their disease genome mapped, but as costs continue to decrease and more information is obtained, the IMP gets closer to finding a cure for malignant mesothelioma.

One of the most significant problems in the treatment of malignant mesothelioma is that the tumor can be resistant to many traditional forms of chemotherapy drugs.  This drug resistance varies from patient to patient.  Hence, weeks and even months of chemotherapy treatment could be wasted on a patient with malignant mesothelioma if that person’s tumor is particularly resistant to the type of drug being administered.

The International Mesothelioma Program (IMP) at Brigham and Women’s Hospital in Boston, Massachusetts is developing a new treatment aid that may assist physicians in prescribing the most appropriate form of chemotherapy for their mesothelioma patients.  This tool is called the Extreme Drug Resistance (EDR) assay.

Extreme Drug Resistance (EDR) Assay

To do an EDR assay, physicians at Brigham and Women’s Hospital remove a mesothelioma tumor fragment during surgery (extrapleural pneumonectomy or pleurectomy/decortication) and send it to the laboratory of Oncotech, Inc. in Tustin, California.  The cultured tumor is then tested against various chemotherapy drugs that are commonly prescribed for malignant mesothelioma.   Brigham and Women’s Hospital has Oncotech expose the tumor to Cisplatin, Gemcitabine, a combination of Cisplatin and Gemcitabine, and Vinorelbine.  As of now, Alimta, which is a drug frequently used to treat mesothelioma, cannot be used in the EDR assay, but the technical problems associated with Alimta in this test are being worked out, according to Dr. William Richards, Operations Director of the Brigham and Women’s Hospital Tissue and Blood Repository.

Oncotech then determines whether the mesothelioma tumor for that particular patient is resistant to each of the chemotherapy drugs or the combination of drugs.  If the EDR assay shows that a cultured tumor is extremely resistant to a particular drug, then there is a 99 percent probability that the tumor in the patient will also be resistant to that drug or drug combination.

Next Step: Clinical Trial Testing

According to Dr. Gavin Gordon, co-director at the Brigham and Women’s Hospital Thoracic Surgery Oncology Laboratory, the EDR assay for malignant mesothelioma must still be tested in a clinical trial for it to be approved as part of the treatment protocol.  There are case reports where the predictive value of the EDR assay has shown a very high correlation between the in vitro test and actual drug resistance in the patient.

In a published case report from the Kobe University Graduate School of Medicine in Japan, physicians used a test similar to the EDR assay called the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) to identify the correct treatment for malignant pleural mesothelioma in a 63 year old woman.  The CD-DST test showed that the patient’s tumor was particularly sensitive in vitro to Gemcitabine and Vinorelbine.  Based on this result, her physicians selected these chemotherapy agents for her treatment.

The EDR assay test could be an invaluable tool in the treatment of malignant pleural mesothelioma and peritoneal mesothelioma, diseases that have shown a wide variability in response to different chemotherapy agents.